The incidence of endometrial cancer is on the rise each year reaching over 60,000 new cases in the US in 2018. Obesity remains a significant public health problem and is a major risk factor for developing endometrial cancer. Although excess estrogen from adipose tissues is thought to predispose a woman from developing endometrial cancer, the protective role of progesterone in obesity is unknown. Studies demonstrate that the excess estrogen theory in obese women does not always hold true particularly in the premenopausal state. We hypothesize that adipose tissue release factors that activate the AKT pathway in endometrial epithelial cells to blunt progesterone receptor (PR) action, thereby increasing the risk of endometrial neoplasia. In this study, we will decipher the actions of PR in the human endometrium in the presence or absence of adipocytes using 3D spheroid cultures in microfluidic systems. These innovative technologies allow us to study for the first time, the effect of adipocytes on the signaling and genomic activities that affect progesterone sensitivity. We will determine how adipocytes affect progesterone driven differentiation and survival of the endometrial organoids and how changes in epigenetics, including DNA methylation and histone marks, affect the ER and PR cistrome. Unbiased sequencing will be done using technologies that allow for deep sequencing of small cell numbers. This research will generate insight into the early changes that may lead to tumorigenesis which will be useful to determine how to effectively prevent endometrial cancer in the obese women who are at high risk.